Project summary and relevance The research program, funded by R01DA16065, is focused on chronic hepatitis C virus (HCV) infection in HIV- infected rug users (DUs). While effective antiretroviral therapy (ART) has reduced overall mortality in HIV- infected DUs, HCV disease is a leading cause of morbidity and mortality. However, like effective ART, HCV treatment leading to sustained virologic response (SVR or cure) may reduce the risk of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC) and death in coinfected individuals. Interferon-based HCV treatments have not been effective due to low treatment uptake and, among those treated, low rates of SVR and high rates of adverse effects. However, HCV treatment is improving rapidly with the advent of peginterferon-sparing, oral regimens of direct acting antivirals (DAAs). Compared to peginterferon based regimens, oral DAA therapy has led to higher SVR rates, improved safety and tolerability, and shorter treatment durations in clinical trials. While promising for the treatment of coinfected DUs, DAA therapy also raises salient clinical questions related to HCV cure in this population: Does HCV cure lead to clinical benefit for individuals and for the population? What behavioral barriers to HCV cure will persist with DAAs and can these barriers be overcome with innovative strategies for DAA delivery? What biological barriers to HCV cure will persist with DAAs and are these impacted by HIV coinfection? In the next funding cycle, we plan to answer these and other questions related to the management of chronic HCV in HIV-infected persons through a series of integrated clinical and translational studies that extend the models of HCV disease natural history and HCV treatment that we and others have developed over the past decade. The specific aims are as follows: Aim 1 is to test the hypothesis that effective HCV treatment antiretroviral therapy reduces the risk of end-stage liver disease, hepatocellular cancer, and death in HIV/HCV coinfected persons. Aim 2 is to test the hypothesis that novel interventions - peer mentoring and contingent financial incentives - will promote health behaviors aimed at reducing the risk of HCV disease in coinfected persons by increasing HCV treatment initiation and adherence to oral DAAs and by decreasing alcohol use. Aim 3 is to test the hypothesis that, compared to patients with HCV monoinfection, patients with HIV/HCV coinfection will have impaired serum and intrahepatic HCV RNA and immune response kinetics during HCV treatment with IFN-free, oral DAAs. The proposed studies will define the impact of HCV treatment with novel DAAs on HCV disease natural history, guide strategies for the effective delivery of the DAAs to overcome behavioral barriers to HCV cure, and, through mechanistic studies understand the impact to HIV coinfection on response to DAAs and HCV eradication to overcome biologic barriers to HCV cure.